Dental caries is a very different disease than it was forty years ago. While caries is declining in general, caries rates in young children (ages 2-5) in the US have been increasing (US GAO, 2008). There is also increasing disparity seen with severe caries occurring disproportionately in the poor and disenfranchised. Notably, individuals living in selected areas of Appalachia have some of the worst oral health indicators in the U.S. The current proposal is a renewal of our ongoing project (R01-DE-014899) to identify factors contributing to the oral health disparity seen in northern Appalachia versus the rest of the nation. The guiding philosophy of our project has been and continues to be that developing strategies to address this disparity requires simultaneous study of multiple risk components (ideally within families) to determine their roles, interactions among them, and their transmissibility patterns. The long-term goal of our program of research is to determine why the Northern Appalachian population is at increased risk of oral disease so that targeted preventive interventions can be designed. One of the most notable results from the first project period was that the disparity in dental caries is evident at an early age; the prevalence of total caries experience in 2 - 5 year olds from our Northern Appalachian study was 144% of the prevalence of comparable children in NHANES, with this disparity diminishing in later age groups. Importantly, we also identified genes in multiple categories (tooth structure, taste preference, and salivary proteins) that are associated with either increased caries risk or protection, sometimes showing different effects in different age groups and/or dentitions. Finally, our microbiological and genetic studies of S. mutans demonstrated extreme genetic diversity and showed that S. mutans alone is unlikely to be the sole caries risk factor; more likely, dynamic changes in the oral microbial ecology are responsible for elevated disease risk. Based on the cross-sectional results, we hypothesize that the mechanisms that lead to disparities develop within the first two years of life. Implicit in this hypothesis is the need to address these questions longitudinally among children before and during the time of greatest risk from three different perspectives: psychosocial, genetic, and microbiological. The aims of this renewal include development of a longitudinal study of dental caries development early in life by recruiting a cohort of pregnant women. We will then utilize both the data collected in the first project period, and new data from the longitudinal cohort to follow up the significant environmental, genetic and microbial results from the first project period.